- Grasso, Catherine S;
- Tsoi, Jennifer;
- Onyshchenko, Mykola;
- Abril-Rodriguez, Gabriel;
- Ross-Macdonald, Petra;
- Wind-Rotolo, Megan;
- Champhekar, Ameya;
- Medina, Egmidio;
- Torrejon, Davis Y;
- Shin, Daniel Sanghoon;
- Tran, Phuong;
- Kim, Yeon Joo;
- Puig-Saus, Cristina;
- Campbell, Katie;
- Vega-Crespo, Agustin;
- Quist, Michael;
- Martignier, Christophe;
- Luke, Jason J;
- Wolchok, Jedd D;
- Johnson, Douglas B;
- Chmielowski, Bartosz;
- Hodi, F Stephen;
- Bhatia, Shailender;
- Sharfman, William;
- Urba, Walter J;
- Slingluff, Craig L;
- Diab, Adi;
- Haanen, John BAG;
- Algarra, Salvador Martin;
- Pardoll, Drew M;
- Anagnostou, Valsamo;
- Topalian, Suzanne L;
- Velculescu, Victor E;
- Speiser, Daniel E;
- Kalbasi, Anusha;
- Ribas, Antoni
We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFN-γ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.